Hospital admissions attributed to adverse drug reactions in tertiary care in Uganda: burden and contributing factors

Background: Adverse drug reactions (ADRs) contribute to the burden of disease globally and of particular concern are ADR-related hospital admissions. Objectives: This study sought to determine the burden, characteristics, contributing factors and patient outcomes of ADRs that were the primary diagnosis linked to hospital admission among inpatients in Uganda. Design: We conducted a cross-sectional secondary analysis of data from a prospective cohort study of adult inpatients aged 18 years and older at Uganda’s Mulago National Referral Hospital from November 2013 to April 2014. Methods: We reviewed clinical charts to identify inpatients with an ADR as one of the admitting diagnoses and, if so, whether or not the hospital admission was primarily attributed to the ADR. Logistic regression was used to determine factors associated with hospital admissions primarily attributed to ADRs. Results: Among 762 inpatients, 14% had ADRs at hospital admission and 7% were primarily hospitalized due to ADRs. A total of 235 ADRs occurred among all inpatients and 57% of the ADRs were the primary diagnosis linked to hospital admission. The majority of ADRs occurred in people living with HIV and were attributed to antiretroviral drugs. HIV infection [aOR (adjusted odds ratio) = 2.97, 95% confidence interval (CI): 1.30–6.77], use of antiretroviral therapy (aOR = 5.46, 95% CI: 2.56–11.68), self-medication (aOR = 2.27, 95% CI: 1.14–4.55) and higher number of drugs used (aOR = 1.13, 95% CI: 1.01–1.26) were independently associated with hospital admissions attributed to ADRs. Conclusion: Antiretroviral drugs were often implicated in ADR-related hospital admissions. HIV infection (whether managed by antiretroviral therapy or not), self-medication and high pill burden were associated with hospital admissions attributable to ADRs. The high HIV burden in Sub-Saharan Africa increases the risk of ADR-related hospitalization implying the need for emphasis on early detection, monitoring and appropriate management of ADRs associated with hospital admission in people living with HIV.


Background
An adverse drug reaction (ADR) is an undesirable medical occurrence that develops after the administration of a drug at doses normally used for treatment. 1 ADRs contribute to the burden of disease and death globally, 2,3 of particular concern are ADR-related hospital admissions. [4][5][6] About 0.2-59.6% of hospital admissions are attributable to ADRs 6-9 and 1.8% of them are fatal in low-and middle-income countries (LMIC). 6 The drugs most frequently implicated in high income countries (HIC) are antithrombotics (oral anticoagulants and antiplatelet agents), non-steroidal anti-inflammatory drugs and cardiovascular medications while antiretrovirals, antibacterials and antituberculosis drugs are the commonest in LMIC. 6,10 Recent studies in Uganda among the admitted elderly implicate cardiovascular drugs, nervous system agents and anti-infective agents as the common cause of ADRs. 11,12 Self-medication has been highlighted to be associated with ADR-related hospitalization in HIC 13,14 ; however, such data are scarce in Sub-Saharan Africa (SSA) where self-medication is rampant.
Being a woman, higher number of administered drugs, comorbidities and the use of antiretroviral therapy are associated with ADR-related hospital admissions in South Africa. 15 Studies conducted in Uganda have reported female gender and history of tobacco use as predictors of medication-related emergency admission among cardiovascular disease patients 12 ; being aged 19-59 years, herbal medicine use, polypharmacy and drug-drug interactions are associated with ADRs among heart failure patients 16 ; and preadmission use of herbal medicines and treatment with six or more conventional medicines during hospitalization are the common risk factors for hospitalacquired suspected ADRs. 17 These studies document the epidemiology of hospital-acquired ADRs and ADRs in the elderly who do not represent the general population. 11,12,[15][16][17] Thus, the burden and associated factors of ADRs linked to hospital admission are not well investigated among inpatients in SSA, particularly in Uganda, where the risk of ADR-related hospitalizations could be heightened by the colliding epidemics of infectious and non-infectious diseases. 18 This study sought to determine the burden, characteristics, contributing factors and patient outcomes of ADRs documented as the primary diagnosis linked to hospital admission among adult inpatients at a tertiary care hospital in Uganda.

Study setting and population
This cross-sectional study is a secondary analysis of data from a previously assembled prospective

Assessment of ADR-related hospital admission
Operationally, an ADR was any undesirable medical occurrence that developed after the administration of a drug. 1 We reviewed clinical charts to identify patients with an ADR as one of the admitting diagnoses and, if so, whether or not the ADR was the primary diagnosis linked to hospital admission. ADRs were characterized by causality, preventability, severity and outcomes. Causality was defined as at least a 'possible' causal relationship between the drug and the event as measured by the Naranjo ADR Probability Scale. 19 Preventability of ADR-related hospital admission was measured by the modified Schumock and Thornton Preventability Scale. 20 We evaluated severity using the Division of AIDS Odds ratios with their 95% confidence intervals (CIs) were computed to determine the contributing factors to ADR-related hospital admission. Age in years, sex, HIV and antiretroviral therapy, antituberculosis therapy, self-medication, history of drug allergies, comorbidity score and number of drugs were evaluated in the multivariable modeling.
Variables with a p-value of 0.05 were considered significantly associated with the outcome -ADR as the primary diagnosis linked to hospital admission.

Characteristics of study inpatients
A total of 762 inpatients aged 18-88 years and median age of 30 years [interquartile range (IQR) of 24-42 years] were enrolled. The majority of inpatients were female (70%, 534/762) and admitted to the medical wards (75%, 571/762). More than a quarter of the inpatients were HIVpositive (30%, 232/762) and 3 in 20 (15%, 113/762) had self-medicated prior to hospital admission. A median of four drugs (IQR of 2-6 drugs) were used during the 1 month prior to hospitalization amongst inpatients with information on the number of drugs used preadmission (83%, 632/762), see Table 1.

Prevalence of ADR-related hospital admission
The overall prevalence of ADR-related hospital admission was 14% (108/762; 95% CI: 12-17%) with ADRs being the documented primary diagnosis linked to hospitalization in 52%  Table 2. There were two fatal cases at hospital admission; one was shortness of breath in a HIV-negative patient and vomiting in a HIVpositive patient.
The five most common ADRs leading to hospitalization were vomiting (18 cases, 13%), anaemia (15 cases, 11%), abdominal pain (12 cases, 9%), headache (12 cases, 9%) and paraesthesias (8 cases, 6%). Vomiting, anaemia and abdominal pain were predominant in HIV-positive inpatients while dizziness, diarrhoea and vomiting were predominant in HIV-negative/unknown inpatients, see Figure 1. Table 3 shows the drugs most commonly implicated in hospital admissions attributable to ADRs. Seventy seven percent (229/296) of the ADRs were a primary diagnosis for hospital admission and were linked to various drugs among the HIV-infected patients. The frequency

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TherapeuTic advances in drug safety   The median length of hospital stay for all inpatients was 5 days (IQR: 3-6 days) and was similar among inpatients admitted for ADRs (median of 5 days; IQR of 3-6 days) versus those admitted for other reasons (median of 5 days; IQR of 3-6 days).

Discussion
In this cross-sectional study conducted among 762 inpatients at Mulago National Referral Hospital, 14% had ADRs at admission and 7% were primarily admitted due to ADRs. A total of 235 ADRs occurred among all inpatients and 135 ADRs among those primarily admitted due to $ Some ADRs were linked to more than one drug and therefore the total frequency of ADRs (296) as the primary diagnosis linked to hospital admission is higher than total number of ADRs encountered (135). ADR, adverse drug reaction.
journals.sagepub.com/home/taw 9 ADRs at admission could substantially decrease. Additionally, lower HIV prevalence and ART use will further lower ADRs at admission. 23  Ceftriaxone was the most reported drug to be used prior to hospital admission among patients presenting with ADRs at admission while herbals, misoprostol, nifedipine and ceftriaxone were the most implicated drugs linked to hospital admission among HIV-negative or unknown HIV status inpatients. These findings are unique to our study population given that gynaecological patients were included in this study. Other studies among admitted elderly patients have reported cardiovascular drugs, nervous system agents and anti-infective agents as the cause of ADRs. 11,12 A study in Uganda by Kiguba et al. 17 reported herbal medicines to be linked to hospital-acquired ADRs. The Uganda treatment guidelines require that misoprostol is administered from a hospital setting; however, it is a common practice for patients to self-medicate with misoprostol to initiate abortion before seeking professional care which causes adverse events such as incomplete abortion, failed abortion, missed abortion, severe anaemia, haemorrhagic shock, sepsis, ectopic pregnancy and ruptured uterus 26 requiring hospital admissions.
Inpatients who self-medicated or used multiple drugs were more likely to be hospitalized due to ADRs, which is consistent with the literature. 4,27 Self-medication is a known risk factor for ADRs. 14,27 Some ADRs are preventable with clinician and pharmacist prescription fidelity, unlike self-medication. Polypharmacy and the use of multiple drugs increases the risk of drug-drug interactions, some of which could be serious, requiring hospitalization. 28 Patient education on the negative effects of self-medication and regulatory restrictions to classified medicines could help reduce self-medication and consequently curb admissions linked to ADRs. Pharmacists are critical in examining complex multiple treatment regimens for inpatients, such as treatments for HIV and comorbidities and advising clinical teams on revising regimens to reduce drug-interactions and ADR-related admissions. 29 This study has important limitations. We assessed ADRs based on clinical judgment and were not able to do laboratory investigations, which could underreport the ADR-related hospital admissions. Some of the associated factors such as history of drug use were based on patient self-report which could have introduced recall bias, possibly leading to increased or decreased strength of the observed associations. Given that this was a cross-sectional study, we were not able to fully establish the causal association of ADRs and hospital admissions. However, we reviewed admissions where ADRs were recorded by the clinicians as being the primary diagnosis linked to hospital admission, more than just ADRs being present at admission. The study findings are limited to the gynaecological and medical settings and might not be generalizable to surgical and paediatric wards. We conducted the study in a single tertiary care hospital that serves referred patients with severe illnesses and a higher number of comorbidities, which makes the findings slightly more difficult to generalize to other patient populations.

Conclusion
Antiretroviral and antituberculosis drugs were often implicated in ADR-related hospital admission. HIV infection (whether managed by ART or not), self-medication and high pill burden were associated with hospital admission attributable to ADRs. The high HIV burden in SSA increases the risk of ADR-related hospitalization implying the need to establish and strengthen systems, such as medication reconciliation, to promote the early detection, monitoring and appropriate management of ADRs linked to hospital admission among HIV-infected people in these settings.